1. Field of the Invention
The present invention relates to a method of inhibiting angiogenesis.
2. Description of the Prior Art
Suppression of angiogenesis is thought to lead to suppression of tumor or cancer growth or metastasis, chronic inflammation, rheumatoid arthritis, retinopathy, diabetic retinopathy, age-related macular degeneration, and the like.
It has been reported that an anti-angiogenic action is present in food ingredients such as shark gristle, epigallocatechin (EGC) and epigallocatechin gallate (EGCG), which are components of green tea, genistein, which is a kind of soybean isoflavone, Agaricus blazei-derived ergosterol, and pyroglutamic acid.
Regarding the anti-angiogenic actions of substances derived from mushrooms, in addition to the aforementioned action of Agaricus blazei-derived ergosterol (Isolation of an anti-angiogenic substance from Agaricus blazei Murill: Its antitumor and antimetastatic actions; Kimura et al.; Cancer Sci., September 2004, vol. 95, no. 9, 758-764), the actions of Trametes versicolor-derived PSK (Inhibitory effect of PSK on angiogenesis.; Wada T, Wakamatsu Y, et al.; Biotherapy 15(3):389-392, 2001) and Sparassis crispa-derived β-1,3-D-glucan have been reported (Anti-angiogenic and Anti-metastatic Effects of β-1,3-D-Glucan Purified from Hanabiratake, Sparassis crispa; Kyosuke Yamamoto, Takashi Kimura et al.; Biol. Pharm. Bull. 32(2) 259-263, 2009).
PS-K is a glycoprotein containing about 15% of protein, and comprising 19 amino acids such as aspartic acid and glutamic acid, characterized by a putative structure of a main chain of α- or β-1,4 bonds with 1 branch per 5 glucose groups at the 3- or 6-position (Host effects of polysaccharides on cancer-bearing animals, with a focus on the action of glycoprotein PS-K from Trametes versicolor; Shigeru Tsukagoshi; Gan To Kagaku Ryoho (Japanese Journal of Cancer and Chemotherapy), vol. 1, no. 2; pp. 251-257, 1974).
Naohito Ohno et al. reported that the antitumor component of Sparassis crispa is 1,3-β-glucan (Antitumor 1,3-β-Glucan from Cultured Fruit Body of Sparassis crispa; Naohito Ohno et al.; Biol. Pharm. Bull. vol. 23, No. 7, 866-872, 2000). Furthermore, Yamamoto et al. reported that the component had a pulmonary metastasis suppressing effect and anti-angiogenic action (Anti-angiogenic and Anti-metastatic Effects of β-1,3-D-Glucan Purified from Hanabiratake, Sparassis crispa; Kyosuke Yamamoto, Takashi Kimura et al.; Biol. Pharm. Bull. 32(2) 259-263, 2009).
The antitumor activity and antitumor immunological action mechanism of a himematsutake-derived (1→6)-β-D-glucan protein complex have already been reported (Inhibitory Action of a (1→6)-β-D-Glucan-Protein Complex (FIII-2-b) Isolated from Agaricus blazei Murill (“Himematsutake”) on Meth A Fibrosarcoma-Bearing Mice and Its Antitumor Mechanism; Hiroko Itoh et al.; Jpn. J. Pharmacol. 66, 265-271, 1994), and a patent application for an antitumor agent was filed as described in JP-A-HEI-2-78630.
This (1→6)-β-D-glucan protein complex (hereinafter also referred to as “the polysaccharide”) is the first substance of its kind obtained from a mushroom, identified as a polysaccharide comprising 50.2% of sugar moiety and 43.3% of protein moiety (Antitumor Activity and Some Properties of Water-insoluble Hetero-glycans from “Himematsutake,” the Fruiting Body of Agaricus blazei Murill; Takashi Mizuno et al.; Agric. Biol. Chem., 54(11), 2897-2905, 1990).
Known β-(1→6)-glucans include pustulan, which is known to occur in the lichen Umbilicaria pustulata; islandic acid (a polysaccharide comprising a main chain of β-(1→6) bond and a few side chains of 1→4 bond), which is obtained from a culture filtrate of Penicillium islandicum; commercially available dextrans with various molecular weights [Dextran] (produced by Pharmacia Co., a glucan comprising a main chain of α-(1→6) bond and a few branched structures); and oat lichenin, which is isolated from the seeds of oat; however, none of these substances possesses antitumor activity against mouse sarcoma 180 or anti-angiogenic action (<Proceedings of Basic Cancer Study Group Symposium> “Criticism on the anticancer effects of polysaccharides”: Study of antineoplastic polysaccharides in lichen, with special reference to Gyrophora esculenta Miyoshi; Yoshihiro Nishikawa; Nippon Rinsho (Japanese Journal of Clinical Medicine), vol. 27, no. 6; pp. 184-188, 1969).
From the above-described findings, it is suggested that the antitumor activities of polysaccharides may be largely influenced by small differences in their molecular structure and stereochemical factors.
While “the polysaccharide” is known to have the properties described above, there has so far been no knowledge that “the polysaccharide” exhibits anti-angiogenic action.
Regarding the safety of himematsutake (the same himematsutake as that from which “the polysaccharide” was isolated [himematsutake having the same gene sequence of the ITS [internal transcribed spacer] of 5.8S rDNA]), himematsutake was verified to be safe in “Safety research with a focus on the mutagenicity of existing natural food additives and the like” (Health Science Special Research Project) by the Head (Makoto Hayashi) of the Division of Genetics and Mutagenesis in the National Institute of Health Sciences et al. Also in a subchronic toxicity study of himematsutake extract in rats, the safety was verified by Yuichi Kuroiwa et al. at the Division of Pathology in the National Institute of Health Sciences (Lack of subchronic toxicity of an aqueous extract of Agaricus blazei Murill in F344 rats; Y. Kuroiwa, et al.; Food and Chemical Toxicology 43(2005) 1047-1053).